More than 70% of the estimated 170 million people worldwide who are infected with hepatitis C virus (HCV) develop chronic infection. Chronic HCV infections can lead to chronic liver disease, cirrhosis, and hepatocellular carcinoma. Chronic HCV infection is the leading indication for liver transplantation in the United States (Alter, H. J. et al. 2000 Semin Liver Dis 20:17-35). Antiviral treatment of HCV is now successful in about half of the cases, but it is expensive, requires long-term treatment, and is associated with serious side effects. There is no vaccine currently available for the prevention of HCV infection.
HCV is a positive-sense RNA virus belonging to the Flaviviridae family. It encodes a single polyprotein of ≈3,000 aa. Through the action of a combination of host and viral proteases, the polyprotein is cleaved into structural proteins (core, E1, E2, and p7) and nonstructural proteins (NS2-NS5B). The two envelope glycoproteins, E1 and E2, are believed to form heterodimers/oligomers on the surface of HCV particles that participate in the process of cell entry (Bartosch, B. et al, 2003 J Exp Med 197:633-642).
The mechanisms that govern the clinical outcomes of HCV infection are not well understood. Whereas cellular immune responses have been considered essential for controlling viral infection (Thimme, R. et al. 2003 Hepatology 37:1472-1474), the role of the humoral immune response remains to be defined. Increasing evidence demonstrates that neutralizing antibodies are present in patients with chronic hepatitis C (Bartosch, B. et al. 2003 Proc Natl Acad Sci USA 100:14199-14204; Meunier, J. C. et al. 2005 Proc Natl Acad Sci USA 102:4560-4565), and that epitopes located within the E2 protein are important for HCV neutralization (Farci, P. et al. 1996 Proc Natl Acad Sci USA 93:15394-15399; Triyatni, M. et al. 2002 Virology 298:124-132; Hsu, M. et al. 2003 Proc Natl Acad Sci USA 100:7271-7276; Logvinoff, C. et al. 2004 Proc Natl Acad Sci USA 101:10149-10154; Owsianka, A. et al. 2005 J Virol 79:11095-11104; Tarr, A. W. et al. 2006 Hepatology 43:592-601; Brown, R. J. et al. 2007 J Gen Virol 88:458-469; Schofield, D. J. et al. 2005 Hepatology 42:1055-1062; Eren, R. et al. 2006 J Viral 80:2654-2664).
Recent data in chimpanzees has shown that an experimental Ig preparation made from anti-HCV-positive plasma (HCIGIV) prevents HCV infection when the preparation is mixed with a virus inoculum ex vivo before infusion (Yu, M. W. et al. 2004 Proc Natl Acad Sci USA 101:7705-7710). Unfortunately, the in vivo efficacy of HCIGIV in both chimpanzees and humans has been disappointing. For example, two clinical studies failed to show that anti-HCV Ig preparations could decrease HCV RNA levels or prevent recurrent infections after liver transplantation (Davis, G. L. et al. 2005 Liver Transpl 11:941-949, Schiano, T. D. et al. 2006 Liver Transpl 12:1381-1389). The need for more treatments for HCV infection is manifest.